Overall Program Summary/Abstract Every year 500,000 women are diagnosed with cervical cancer and 200,000 die from it worldwide. The overall goal of our cervical cancer SPORE is, in the next 5 years, to better reach and protect the next generation of women from oncogenic HPV infection, and to develop novel vaccines to improve treatment outcomes of patients with persistent HPV infection, HPV-associated precancer, and cervical cancer. Vaccines represent the most cost-effective and successful public health intervention. We include four vaccine projects in this SPORE program based upon the success of prophylactic HPV vaccination for primary prevention of cervical cancer, and advances in understanding of cellular immunology, including the mechanisms of spontaneous viral clearance, the impact of HIV, and the licensure of pembrolizumab for treatment of recurrent/progressing cervical cancer. The power of secondary prevention is evident from the success of population-based cytologic screening programs and ablative treatment of high-grade cervical intraepithelial neoplasia. Simultaneously, we recognize the continued need and cost of cervical screening even in vaccinated patients, and for prevalent disease in the unvaccinated generations, and disadvantaged populations for the next decades. The licensure of several screening tests for oncogenic HPV infection and genotyping is revolutionizing screening, and HPV testing will likely be used for upfront screening. This will provide an opportunity to eliminate persistent oncogenic HPV infections prior to progression to dysplasia and for personalized cancer treatment by therapeutic HPV vaccination. It is clear that successful prevention and treatment, and indeed eradication of cervical cancer, can be a reality by improving access to, and the breadth of prophylactic HPV vaccination, and combining current screening and treatment modalities with novel therapeutic HPV vaccine-based approaches. Therefore, there are three overarching goals in this SPORE: 1) PRIMARY PREVENTION to reduce the global incidence of cervical cancer by improving access to prophylactic vaccination through the development of a low- cost, thermostable virus-like particle vaccine that effectively prevents infection by all oncogenic HPV types (Project 1), 2) SECONDARY PREVENTION by treating persistent HPV infection (Project 2) and associated precancer lesions (Project 3) using innovative therapeutic HPV vaccines, and 3) Improving CANCER TREATMENT by complementing existing treatments (chemoradiation and immune checkpoint blockade) with therapeutic HPV vaccination (Project 4). This program is supported by an Administrative/Communication Core (Core A), a Biostatistics/Bioinformatics Core (Core B), a Tissue/Pathology/Immunology Core (Core C), and innovates and renews through a Developmental Research Program (DRP) and a Career Enhancement Program (CEP). Together, our SPORE will expand options for the control of HPV-associated disease at multiple points during the progression of cervical cancer.